TRANS-3-BENZYL-4-HYDROXY-7-CHROMANYLBENZOIC ACID-DERIVATIVES AS ANTAGONISTS OF THE LEUKOTRIENE B-4 (LTB4) RECEPTOR

The SAR of a series of 2-(7-chromanyl)benzoic acids has been investiga ted with the aim of identifying potent and selective LTB4 receptor ant agonists that maintain potency in complex biological fluids. We found optimal activity in derivatives with electron-withdrawing groups in th e benzoic acid ring and with an unsubstituted C-3 benzyl group on the chromanol nucleus. While compounds containing a 3-(4-phenyl)benzyl chr omanol substituent were potent LTB4 receptor antagonists, the increase d lipophilicity imparted by the additional phenyl substituent led to d ecreased potency in the presence of plasma proteins. From among the po tent compounds identified, CP-195543, the 5'-trifluoromethyl 3-benzyl chromanol, was selected for development. (C) 1998 Elsevier Science Ltd . All rights reserved.